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Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat

Item Type:Article
Title:Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat
Creators Name:Rubattu, S. and Lee-Kirsch, M.A. and DePaolis, P. and Giliberti, R. and Gigante, B. and Lombardi, A. and Volpe, M. and Lindpaintner, K.
Abstract:Through the genotype/phenotype cosegregation analysis of an F(2) intercross, from the crossbreeding of stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHR), we previously identified a quantitative trait locus for stroke on rat chromosome 5 (STR2) that colocalized with the genes encoding atrial and brain natriuretic peptides (ANP and BNP) and conferred a stroke-delaying effect. To further characterize ANP and BNP as candidates for stroke, we performed additional studies. Comparative sequence analysis revealed point mutations in both the coding and regulatory regions of ANP, whereas no interstrain differences were found for BNP. In in vitro studies in COS-7 and AtT-20 cells that were performed to test the relevance of a G-->A substitution at position 1125, a Gly-->Ser transposition in the SHRSP pro-ANP peptide resulted in different posttranslational processing of the SHRSP ANP gene product that was also associated with higher cGMP production (P<0.05). Furthermore, an analysis of a 5' end mutation affecting a PEA2 regulatory binding site in the 5' untranslated regulatory sequence of SHRSP ANP demonstrated a significantly lower ANP promoter activation in endothelial cells (P<0.05 versus the SHR ANP). In addition, the expression of ANP was significantly reduced in the brain, but not in the atria, of SHRSP compared with SHR (P<0.0001). No differences were detected with regard to BNP expression. The present results reveal substantial differences in ANP, but not BNP, structure and product among SHR and SHRSP, which supports a role of ANP in the pathogenesis of stroke in the SHRSP animal model.
Keywords:Genetics, Atrial Natriuretic Peptide, Stroke, Natriuretic Peptide, Animals, Rats
Source:Circulation Research
ISSN:0009-7330
Publisher:American Heart Association (U.S.A.)
Volume:85
Number:10
Page Range:900-905
Date:12 November 1999
Official Publication:http://circres.ahajournals.org/cgi/content/abstract/85/10/900
PubMed:View item in PubMed

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